Fitting a neural prosthesis using impedance and electrode height

ABSTRACT

The invention is a method of automatically adjusting an electrode array to the neural characteristics of an individual subject. The response to electrical neural stimulation varies from subject to subject. Measure of impedance may be used to predict the electrode height from the neural tissue and, thereby, predict the threshold of perception. Alternatively, electrode height may be measured directly to predict the threshold of perception. Also, impedance measurement may be used to quickly identify defective electrodes and proper electrode placement.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application60/741,810, filed Dec. 1, 2005, for Correlation of Electrode Height,Stimulation Threshold and Impedance in a Retinal Prosthetic Implant, and60/853,477, filed Oct. 20, 2006, for Real Time Electrode ImpedanceMeasurement and Data Display for an Implantable Device. This applicationis related to and incorporates herein by reference, U.S. patentapplication Ser. Nos. 10/864,590, filed Jun. 8, 2004, for AutomaticFitting for a Visual Prosthesis, and 11/357,680, filed Feb. 16, 2006,for Fitting of Brightness in a Visual Prosthesis.

GOVERNMENT RIGHTS NOTICE

This invention was made with government support under grant No.R24EY12893-01, awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The present invention is generally directed to neural stimulation andmore specifically to an improved method of optimizing neural stimulationlevels for artificial vision.

BACKGROUND OF THE INVENTION

In 1755 LeRoy passed the electrical discharge of a Leyden jar throughthe eye orbit of a man who was blind from cataracts and the subject saw“flames passing rapidly downwards.” Ever since, there has been afascination with electrically elicited visual perception. The generalconcept of electrical stimulation of retinal cells to produce theseflashes of light or phosphenes has been known for quite some time. Basedon these general principles, some early attempts at devising aprosthesis for aiding the visually impaired have included attachingelectrodes to the head or eyelids of subjects. While some of these earlyattempts met with some limited success, these early prosthetic deviceswere large, bulky and could not produce adequate simulated vision totruly aid the visually impaired.

In the early 1930's, Foerster investigated the effect of electricallystimulating the exposed occipital pole of one cerebral hemisphere. Hefound that, when a point at the extreme occipital pole was stimulated,the subject perceived a small spot of light directly in front andmotionless (a phosphene). Subsequently, Brindley and Lewin (1968)thoroughly studied electrical stimulation of the human occipital(visual) cortex. By varying the stimulation parameters, theseinvestigators described in detail the location of the phosphenesproduced relative to the specific region of the occipital cortexstimulated. These experiments demonstrated: (1) the consistent shape andposition of phosphenes; (2) that increased stimulation pulse durationmade phosphenes brighter; and (3) that there was no detectableinteraction between neighboring electrodes which were as close as 2.4 mmapart.

As intraocular surgical techniques have advanced, it has become possibleto apply stimulation on small groups and even on individual retinalcells to generate focused phosphenes through devices implanted withinthe eye itself. This has sparked renewed interest in developing methodsand apparatuses to aid the visually impaired. Specifically, great efforthas been expended in the area of intraocular retinal prosthesis devicesin an effort to restore vision in cases where blindness is caused byphotoreceptor degenerative retinal diseases such as retinitis pigmentosaand age related macular degeneration which affect millions of peopleworldwide.

Neural tissue can be artificially stimulated and activated by prostheticdevices that pass pulses of electrical current through electrodes onsuch a device. The passage of current causes changes in electricalpotentials across visual neuronal membranes, which can initiate visualneuron action potentials, which are the means of information transfer inthe nervous system.

Based on this mechanism, it is possible to input information into thenervous system by coding the information as a sequence of electricalpulses which are relayed to the nervous system via the prostheticdevice. In this way, it is possible to provide artificial sensationsincluding vision.

One typical application of neural tissue stimulation is in therehabilitation of the blind. Some forms of blindness involve selectiveloss of the light sensitive transducers of the retina. Other retinalneurons remain viable, however, and may be activated in the mannerdescribed above by placement of a prosthetic electrode device on theinner (toward the vitreous) retinal surface (epiretinal). This placementmust be mechanically stable, minimize the distance between the deviceelectrodes and the visual neurons, and avoid undue compression of thevisual neurons.

In 1986, Bullara (U.S. Pat. No. 4,573,481) patented an electrodeassembly for surgical implantation on a nerve. The matrix was siliconewith embedded iridium electrodes. The assembly fit around a nerve tostimulate it.

Dawson and Radtke stimulated cat's retina by direct electricalstimulation of the retinal ganglion cell layer. These experimentersplaced nine and then fourteen electrodes upon the inner retinal layer(i.e., primarily the ganglion cell layer) of two cats. Their experimentssuggested that electrical stimulation of the retina with 30 to 100 uAcurrent resulted in visual cortical responses. These experiments werecarried out with needle-shaped electrodes that penetrated the surface ofthe retina (see also U.S. Pat. No. 4,628,933 to Michelson).

The Michelson '933 apparatus includes an array of photosensitive deviceson its surface that are connected to a plurality of electrodespositioned on the opposite surface of the device to stimulate theretina. These electrodes are disposed to form an array similar to a “bedof nails” having conductors which impinge directly on the retina tostimulate the retinal cells. U.S. Pat. No. 4,837,049 to Byers describesspike electrodes for neural stimulation. Each spike electrode piercesneural tissue for better electrical contact. U.S. Pat. No. 5,215,088 toNorman describes an array of spike electrodes for cortical stimulation.Each spike pierces cortical tissue for better electrical contact.

The art of implanting an intraocular prosthetic device to electricallystimulate the retina was advanced with the introduction of retinal tacksin retinal surgery. De Juan, et al. at Duke University Eye Centerinserted retinal tacks into retinas in an effort to reattach retinasthat had detached from the underlying choroid, which is the source ofblood supply for the outer retina and thus the photoreceptors. See,e.g., E. de Juan, et al., 99 Am. J. Ophthalmol. 272 (1985). Theseretinal tacks have proved to be biocompatible and remain embedded in theretina, and choroid/sclera, effectively pinning the retina against thechoroid and the posterior aspects of the globe. Retinal tacks are oneway to attach a retinal array to the retina. U.S. Pat. No. 5,109,844 tode Juan describes a flat electrode array placed against the retina forvisual stimulation. U.S. Pat. No. 5,935,155 to Humayun describes aretinal prosthesis for use with the flat retinal array described in deJuan.

In addition to the electrode arrays described above, there are severalmethods of mapping a high resolution camera image to a lower resolutionelectrode array. U.S. Pat. No. 6,400,989 to Eckmiller describesspatio-temporal filters for controlling patterns of stimulation in anarray of electrodes. The assignee of the present applications has threerelated U.S. patent application Ser. Nos. 09/515,373, filed Feb. 29,2000, entitled Retinal Color Prosthesis for Color Sight Restoration;09/851,268, filed May 7, 2001, entitled Method, Apparatus and System forImproved Electronic Acuity and Perceived Resolution Using Eye JitterLike Motion; and Attorney Docket S242-USA, filed on current dateherewith, entitled User Directed Pixel Re-Mapping. All threeapplications are incorporated herein by reference.

Each person's response to neural stimulation differs. In the case ofretinal stimulation, a person's response varies from one region of theretina to another. In general, the retina is more sensitive closer tothe fovea. Responses are also very sensitive to the distance of theelectrode array from the retinal surface. Any stimulation with magnitudeless than the threshold of perception is ineffective in producing animage. Stimulation beyond a maximum level will be painful and possiblydangerous to the subject. It is therefore, important to map any videoimage to a range of stimulation values between the minimum and maximumfor each individual electrode. With a simple retinal prosthesis, it ispossible to adjust the stimulation manually by stimulating andquestioning the subject. As resolution (number of electrodes) increases,it is tedious or impossible to adjust each electrode by stimulating andeliciting a subject response.

A manual method of fitting or adjusting the stimulation levels of anauditory prosthesis is described in U.S. Pat. No. 4,577,642, Hochmair etal. Hochmair adjusts the auditory prosthesis by having a user compare areceived signal with a visual representation of that signal.

A more automated system of adjusting an auditory prosthesis using middleear reflex and evoked potentials is described in U.S. Pat. No.6,157,861, Faltys et al. An alternate method of adjusting an auditoryprosthesis using the stapedius muscle is described in U.S. Pat. No.6,205,360, Carter et al. A third alternative using myogenic evokedresponse is disclosed in U.S. Pat. No. 6,415,185, Maltan.

U.S. Pat. No. 6,208,894, Schulman describes a network of neuralstimulators and recorders implanted throughout the body communicatingwirelessly with a central control unit. U.S. Pat. No. 6,522,928,Whitehurst, describes an improvement on the system described in Schulmanusing function electro stimulation also know as adaptive deltamodulation to communicate between the implanted devices and the centralcontrol unit.

The greatest dynamic range is achieved by setting the minimumstimulation at the threshold of perception and the maximum stimulationlevel approaching the pain threshold. It is unpleasant for a subject tofirst concentrate to detect the minimum perception and then be subjectedto stimulation near the threshold of pain.

One major concern in the field has been that the amount of electricalcharge needed to elicit light percepts might be too high to permitlong-term stimulation without damage to the retina. A second concern isthat the current required to elicit percepts may fluctuate over time,due to either neurophysiological change or damage to the retina itself,electrochemical changes on the electrode surface, or instability ofposition of the array on the retinal surface.

Previous short-term acute studies (lasting less than 3 hours) found thatlocalized retinal electrical stimulation of blind subjects with RP andAMD resulted in discrete percepts, however the amount of electricalcurrent required to elicit a response was relatively large compared toanimal studies examining retinal responses to electrical stimulation.One likely explanation for these high thresholds is that it is extremelydifficult to lay an electrode array flush on the retinal surface duringan acute trial. However an alternative possibility was that the highelectrical thresholds found in human trials were due to the effects ofretinal degeneration which include both loss of cells and severerewiring within the inner layers of the retina.

The human retina includes about four million individual photoreceptors.An effective visual prosthesis may include thousands of electrodes. Anautomated system is needed to adjust individual electrodes in a visualprosthesis for maximum benefit without the need for subject interactionin a long and difficult process.

SUMMARY OF THE INVENTION

The invention is a method of automatically adjusting an electrode arrayto the neural characteristics of an individual subject. The response toelectrical neural stimulation varies from subject to subject. Measure ofimpedance may be used to predict the electrode height from the neuraltissue and, thereby, predict the threshold of perception. Alternatively,electrode height may be measured directly to predict the threshold ofperception. Also, impedance measurement may be used to quickly identifydefective electrodes and proper electrode placement.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of the implanted portion of the preferredretinal prosthesis.

FIG. 2 a is a fundus photo showing and electrode array on the retina.

FIG. 2 b is a Cross-sectional OCT image of the retina and electrodearray shown in FIG. 2 a.

FIG. 3 a is a graph showing OCT distance estimate by two observers.

FIG. 3 b is a graph showing OCT retinal thickness estimates by twoobservers.

FIG. 4 a-f are a set of six bar graphs showing perception thresholdmeasurements in six subjects.

FIG. 5 a-c are graphs showing the relationship between electrodediameter and threshold of perception.

FIG. 6 a-v are graphs showing the relationship of time to threshold ofperception, impedance, electrode height, and retinal thickness.

FIG. 7 a-f are graphs showing the correlation of threshold ofperception, impedance and retinal thickness.

FIG. 8 depicts a screen showing the preferred method of communicatingelectrode impedance.

FIG. 9 is a flowchart of the impedance test.

FIG. 10 a-c are a flowchart of the automated impedance measurement andelectrode deactivation procedure.

FIG. 11 depicts a stimulation pulse further illustrating themeasurements described in FIG. 10.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description is of the best mode presently contemplated forcarrying out the invention. This description is not to be taken in alimiting sense, but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe determined with reference to the claims.

FIG. 1 shows a perspective view of the implanted portion of thepreferred retinal prosthesis. A flexible circuit 1 includes a flexiblecircuit electrode array 10 which is mounted by a retinal tack (notshown) or similar means to the epiretinal surface. The flexible circuitelectrode array 10 is electrically coupled by a flexible circuit cable12, which pierces the sclera and is electrically coupled to anelectronics package 14, external to the sclera.

The electronics package 14 is electrically coupled to a secondaryinductive coil 16. Preferably the secondary inductive coil 16 is madefrom wound wire. Alternatively, the secondary inductive coil 16 may bemade from a flexible circuit polymer sandwich with wire traces depositedbetween layers of flexible circuit polymer. The electronics package 14and secondary inductive coil 16 are held together by a molded body 18.The molded body 18 may also include suture tabs 20. The molded body 18narrows to form a strap 22 which surrounds the sclera and holds themolded body 18, secondary inductive coil 16, and electronics package 14in place. The molded body 18, suture tabs 20 and strap 22 are preferablyan integrated unit made of silicone elastomer. Silicone elastomer can beformed in a pre-curved shape to match the curvature of a typical sclera.However, silicone remains flexible enough to accommodate implantationand to adapt to variations in the curvature of an individual sclera. Thesecondary inductive coil 16 and molded body 18 are preferably ovalshaped. A strap 22 can better support an oval shaped coil.

The preferred prosthesis includes an external portion (not shown) whichincludes a camera, video processing circuitry and an external coil forsending power and stimulation data to the implanted portion.

The electronics package 14 converts a radio frequency signal intoelectrical stimulation patterns. Input signals are provided via aninductive wireless link using an external antenna magnetically alignedover the secondary inductive coil 16. The desired pulse pattern is sentto a custom-built video processing unit that codes the data as a serialdata stream, and transmits it to the implant via the wireless link. Inaddition, the transmitted signal supplied power to the implant. Areverse telemetry function in the implant allows direct measurement ofimpedance of each electrode. The subjects' un-operated eye is patchedduring all tests to ensure that subjects' thresholds are not affected byresidual vision in the un-operated eye. While 1 kHz is used in thepreferred embodiment, it should be noted that higher frequencies producemore accurate results. 1 kHz is a compromise between impedance accuracyand hardware complexity. It is further possible to determine impedanceby a single biphasic pulse. Pulses may also take various wave forms suchas sinusoidal or square wave.

Optical Coherence Tomography (OCT)

Optical coherence tomography may be used to measure the distance of theelectrode array from the retinal surface and to measure retinalthickness. The underlying principle of OCT imaging is much like that ofultrasound, except that light is used instead of sound, thus permittingmeasurements resolved to the scale of ≦10 μm. Cross-sectional images ofretinal tissue across multiple depth planes may be inferred from theprofile of near infra-red backscattered light.

FIG. 2 a shows a fundus image of an intraocular stimulating array withthe OCT imaging light source visible 56. The arrow 58 represents thedirection along which imaging is carried out. FIG. 2 b shows the imageof the cross-section of the retina that lies under the OCT imaging lightsource of 2 a. Broad shadows are cast by the electrodes 60, and narrowshadows 62 are either due to the imaging light source passing across theedge of the electrode (as is the case in electrode 3 in this example) orare cast by individual wires within the array (note that wires also passabove individual electrodes). Corresponding electrodes are labeledacross the figure. The small deviation between the fundus and OCT imageis due to small eye-movements in the very short time interval thatseparates acquisition of the two images.

As shown in FIG. 2 b, the distance of the electrode array from theretinal surface is defined as the distance from the top of eachelectrode to the inner surface of the ganglion cell layer arrows 64.Measurements therefore include the electrode thickness, which variesbetween 80-120 μm depending on the exact cross-section of the electrodeover which the OCT measurement is taken. The thickness of the retina isdefined as the distance from the inner surface of the retinal pigmentepithelium to the surface of the internal limiting membrane 66.

As can be seen in FIG. 2, it was not always easy to determine the exactposition of the top of the electrode, the surface of the internallimiting membrane, or the inner surface of the retinal pigmentepithelium, and these judgments relied heavily on the experience of theexperimenter. Two experimenters performed these analyses with the helpof custom software written in Matlab. Such subjective measures could beautomated through computer imaging and image recognition software tomake this subjective measure objective.

We cross-validated the judgments of these experimenters by having bothexperimenters analyze the same subset of 43 estimates of electrodedistance and retinal thickness. FIG. 3 a plots the first experimenter'sjudgments of electrode distance from the retinal surface along thex-axis, and the second experimenter's judgments along the y-axis. If twoexperimenters' judgments were perfectly correlated the data would fallalong the dashed line of slope 1. The actual best fitting regressionline had a slope of 1.06, as shown by the solid line. A Monte-Carloprocedure in which each judgment was randomly assigned to anexperimenter is used to assess whether the best-fitting regression slopefor these data differed significantly from 1. Performance acrossobservers was strongly correlated (r²=0.78; p<0.01) and the differencebetween the best-fitting regression line and a line of slope 1 was notsignificant (p>0.05, two-tailed). FIG. 3 b plots the firstexperimenter's judgments of retinal thickness along the x-axis, and thesecond experimenter's judgments along the y-axis. Once again, if the twoexperimenters' judgments were perfectly correlated the data would fallalong the dashed line of slope 1. The actual best fitting regressionline had a slope of 0.83, as shown by the solid line. Once again,performance across observers was strongly correlated (r²=0.85; p<0.01)and a Monte-Carlo procedure demonstrated that the best-fittingregression slope did not differ significantly from 1 (p>0.05,two-tailed).

These measurements demonstrate that inter-experimenter differences inmeasurement between experimenters were small, and are unlikely to resultin large errors or biases in estimates of either electrode distance orretinal thickness. The high consistency across experimentersdemonstrates that trained observers can make consistent judgments aboutelectrode distance and retinal thickness on the basis of our OCT images.

Impedance

Electrode impedance provides a measure of current resistance that isaffected by both the electrochemical properties and size of theelectrode itself, and the properties of the tissue surrounding theelectrode. We can determine, in retinal implants, that impedance isassociated with array position on the retinal surface. In particular,impedance is inversely proportional to electrode height. Note thatelectrode height as used herein refers to the distance between theretinal surface and the electrode.

Impedance is measured using software with a back telemetry program. Thesoftware uses a same diagnostic function of the implant by sequentiallygenerating a 1 kHz, 10 μA sine wave on each electrode, recording theresulting voltage drop, calculating the impedance modulus in kΩ andtransmitting this information from the implant to the external systemvia a reverse telemetry link. Impedance measurements are taken at thebeginning and the end of each stimulating session and may be takenduring surgery.

Perceptual Thresholds

Perceptual thresholds are the amount of current needed to detect a pulseon 50% of trials, corrected for false alarms, i.e. the amount of currentneeded to elicit visible percepts of light. We can measure detectionthresholds for each electrode using a “standard pulse” consisting of acharge-balanced 0.975 ms cathodic pulse followed by a 0.975 ms anodicpulse with a 0.975 ms inter-pulse delay between cathodic and anodiccomponents. All pulse waveforms were biphasic charge balanced.

During this period a yes-no procedure was used, with half the trialsbeing blank trials. The stimulation intensity of the test pulse wasvaried using a three-up-one-down staircase, and each threshold was basedon approximately 100 trials (generally 50 trials are adequate toestimate threshold with reasonable accuracy). After November 2004 thisprocedure was automated, and subjects responded whether or not they sawa stimulus on each trial via key press.

We validated that each change in procedure did not lead to a discernablechange in estimated thresholds by measuring threshold using both the oldand new technique on a number of electrodes before changing our protocolto the new technique.

Results

Thresholds

Phosphene appearance near threshold is typically white or yellow, andphosphenes are reported as being round or oval in shape. In these casesan increase in the stimulation current results in subjects seeing alight spot in the same location. Phosphenes at threshold were notuncomfortable or unpleasant.

Mean thresholds over the entire period over which we collected data foreach subject are shown for each electrode and subject in FIG. 4. Foreach subject, electrodes are ordered from least to most sensitive alongthe x-axis. Gray and black bars represent electrodes with a diameter of250 and 500 μm respectively. Threshold current required for the subjectto see a pulse on 50% of trials corrected for false alarms is shownalong the y-axis. Note the dramatic change of scale along the y-axisacross subjects. Most of the variation in threshold across repeatedmeasurements (single error bars are shown) is due to variation inthreshold over time as opposed to measurement error, as illustrated inFIG. 6; measured thresholds taken within a few days of each other tendto be very close in value.

Thresholds as a Function of Electrode Size

Subjects S4-6 were implanted with checkerboard arrays in whichelectrodes of 250 and 500 μm alternated in the array (see FIG. 2 a). Wecompared mean threshold between these two electrode sizes for eachsubject. Other data shown suggest that the distance of the array fromthe retinal surface has a dramatic effect on thresholds. However, thecheckerboard arrangement used in these three subjects provided a way ofcrudely factoring out the effects of electrode distance, since anyvariation in the distance of electrodes was likely to average out acrossthe two electrodes sizes. To our surprise, we found that electrode sizedid not affect current threshold (Two-factor, subject×electrode size,ANOVA, p>0.05 F=0.367), see FIG. 5 a.

It has previously been shown within in vitro animal preparations thatthe log threshold current required to elicit spikes within in vitroretina is linearly correlated with log electrode area. FIG. 5 b comparesmean thresholds. It is possible that a wider range of electrode sizeswould make threshold differences as a function of electrode size moreapparent. It is also possible, given the large electrode sizes used inthis experiment that current density is highest in a ring around theelectrode edges. Smaller electrodes would be expected to have more evencurrent distribution across the electrode surface.

As illustrated in FIG. 5 b, previous human studies, which were mainlycarried out in acute preparations, show remarkable variability inthreshold. There are multiple potential causes for this variability.Under acute conditions subject concentration and electrode position aredifficult to control and it is only possible to collect a small numberof trials. Even where data were collected chronically, reportedthresholds were based on a small number of trials, and different sizesof electrodes were not implanted within the same subjects, therebyconfounding array position and inter-subject variability with electrodesize.

The data reported here are lower than those reported in previousstudies, and demonstrate that the current intensity levels required toelicit percepts in humans are consistent with the current intensitiesrequired within in vitro experiments using similar electrode sizes. Oursubjects are surprisingly sensitive, given that the criterion used todefine threshold used within in vitro studies is current stimulationlevel will reliably elicit spike in a single cell. However it has beenpreviously shown that subjects with normal vision can reliably detect asingle photon of light, suggesting that a very small increase over thebaseline firing rate of ganglion cells is probably sufficient to mediatebehavioral detection. It is also possible that degenerated human retinais more sensitive to electrical stimulation than the non-degeneraterodent retinal models generally used for in vitro experiments.

Thresholds Over Time

Thresholds do not remain stable over time, as shown in the first columnof FIG. 6. On the whole, subject thresholds tended to increasepostoperatively, consistent with the electrode array lifting off theretina. For each subject we calculated the best-fitting linearregression over time across all electrodes. As described above, S2'sarray separated from the retina after 11 months due to the subjectfalling and bumping her head and the array was then reattached. For thissubject we calculated separate linear regressions for each arrayattachment.

In all subjects except S1 there was a significant tendency for theslopes of the linear regression describing threshold as a function oftime for each individual electrode to have a positive slope (two-tailedt-test, p<0.05). For S1 the tendency for slopes to be positive fell justbelow significance (p=0.057, t=2.061). While reasonably well fit by alinear regression, each subject showed individual patterns of thresholdinstability over time. As discussed below, we believe that these changesin threshold are mainly driven by changes in the distance of theelectrode array from the retinal surface.

Impedances

As would be expected, impedance did vary with electrode size, as shownin FIG. 5 c (Two-factor ANOVA with replication, (p<0.001, F=146.650).After implantation we also see significant variability in impedance overtime, as shown in the second column of FIG. 6. On the whole, subjectimpedances tended to decrease postoperatively during the weeks andmonths after implantation, consistent with the electrode array liftingoff the retina. These data, together with that from OCT measurements,suggests that for the relatively thick and heavy arrays used in thisimplantation a single tack was not sufficient to maintain the array in astable position flush to the retinal surface.

For each subject we calculated the best-fitting linear regression overtime across all electrodes. For all subjects except S5, the slopes ofthe linear regressions describing impedance as a function of time foreach electrode had a significant tendency to decrease over time(p<0.05). For S5 there was a non-significant tendency for slopes to benegative (p=0.122, t=−1.6416). While reasonably well fit by a linearregression, each subject showed an individual patterns of impedanceinstability over time. As discussed below, we believe that these changesin impedance are mainly driven by changes in the distance of theelectrode array from the retinal surface.

Array Position and Retinal Thickness

The two right columns of FIG. 6 show measured distances of the arrayform the retinal surface and measured retinal thickness respectively.Note that estimates of electrode distance from the retina include thethickness of the electrode (approximately 80-120 μm), as described inMethods above. Occasionally there were multiple OCT images of the sameelectrode taken on the same day. In these cases measurements ofelectrode distance and retinal thickness for that electrode wereaveraged and standard errors calculated. Due to the difficulty incollecting these measurements, only a subset of electrodes were measuredon any given date. No clear trend over time is visible across subjectsfor either electrode distance or retinal thickness.

The Relationship Between Threshold, Impedance, Electrode Distance andRetinal Thickness.

FIG. 7 a-f shows the relationship between threshold, impedance,electrode distance and retinal thickness. In all cases data are plottedon log-log axes. To find corresponding measurements, we partitioned ourdata into 30 day time periods. So for example, a given data pointcomparing impedance and threshold values might represent the averageacross several impedance measurements and several threshold measurementsboth collected within the same 30 day time period (e.g. post-operativedays 50-79 inclusive). All data within FIG. 7 are based on the same30-day time window approach. Data therefore include repeated thresholdand impedance measurements on each electrode. Electrode height andretinal thickness measurements were taken less frequently, but the sameapproach still applied; electrode height and retinal thickness estimateswere compared to impedance or threshold measurements taken within thesame 30 day time window as the OCT measurement.

As shown in FIG. 7 a, across subjects there was a significant slope (s)of −1 (s=−1.0, p<0.001) between threshold and impedance. (logthreshold=1/log impedance+k) on log axes. The linear regression slope onlog-log axes was significantly less than zero in 5 of the 6 individualsubjects (S1, s=−14.1, p<0.001; S2, s=−15.8, p<0.001; S3, s=−4.4,p<0.001; S4, s=−6.15, p<0.001; S6, s=−0.578, p<0.001).

As shown in FIG. 7 b, across subjects there is a positive correlationbetween log electrode distance from the retina and log threshold(s=2.21, p<0.001). However the slope was significantly greater than zeroin only 1 of the individual subjects for which OCT data were available(S2, s=1.954, p<0.001). There was, therefore, a strong relationshipbetween estimated electrode distance and threshold across subjects, butthis correlation was not apparent within individual subjects.

It has been suggested that, in retinal stimulation, the electric fieldmay diminish with the square of the distance from the electrode, asoccurs in an isotropic medium with distant boundaries. If so, thresholdsshould increase with the square of the distance of the electrode fromthe retinal surface. Recent electrophysiological data do indeed findthat spike thresholds increase with distance according to a square lawwithin in vitro retinal preparations. The solid line that overlaps thebest-fit dashed line shows predicted regression based on the square ofthe distance (the intercept was minimized using a maximum likelihoodprocedure). The good fit suggests that, for our array configuration,modeling the electric field current as an isotropic medium with distantboundaries may provide a reasonable model for electrical stimulationthresholds.

As shown in FIG. 7 c, across subjects there is negative correlationbetween log impedance and log electrode distance (s=−1.1, p<0.001). Thelinear regression slope on log-log axes was significantly less than zeroin only 2 of the 5 individual subjects for which OCT data were available(S2, s=−0.08, p<0.001; S6, s=−0.3, p<0.001). Therefore there was onceagain a strong relationship between estimated electrode distance andimpedance across subjects, but this correlation was again not clearwithin individual subjects.

As shown in FIG. 7 d, there was a very shallow but significant negativecorrelation between electrode distance and retinal thickness (s=−0.18,p<0.05, note that this significance level does not remain significantafter correction for multiple comparisons) across subjects. One possibleexplanation for this weak correlation may have been that the surgeon mayhave been more conservative in the placement of the array in subjectswhose retinal surface appeared more fragile. S5 showed a significantpositive slope relating electrode distance from the retinal surface andretinal thickness (S5, s=1.213, p<0.01, p<0.05 after Bonferronicorrection), which may have been due to a slight compression of theretinal surface by the array in this subject. Alternatively it ispossible that the high currents that are necessary when there is a largedistance between the array and the retina resulted in a reduction of thethickness of the retinal surface.

As shown in FIG. 7 e, across subjects there was no correlation betweenretinal thickness and impedance (p<0.05). Within the 5 individualsubjects, two subjects had a shallow negative correlation (S3, s=−0.3,p<0.001; S6, s=−0.1, p<0.001) and a third showed a shallow positivecorrelation (S4, s=0.04, p<0.001).

As shown in FIG. 7 f, across subjects there was no correlation betweenretinal thickness and threshold (p<0.05). One subject showed asignificant positive correlation (S6, s=0.4, p<0.01). These leftmostthree figures (d, e, f) suggest that there was little compression of theretina by the array, and what compression there was did not have a majoraffect on either thresholds or impedance.

Discussion

Consistent with the hypothesis that the high thresholds reported inprevious human acute studies were due to distance between the electrodearray and the retinal surface, we find that our thresholds aresignificantly lower than had been previously reported for human retinalelectrical stimulation. Indeed, in our later subjects electricalstimulation thresholds are comparable to those reported in the animal invitro electrophysiological literature. This suggests that retinaldegeneration due to RP does not result in a significant elevation of theelectrical stimulation threshold.

We found that thresholds were the same for 250 and 500 μm electrodes.This is in contradiction to a recent literature review by Sekirnjak etal. who found, across a wide range of in vitro and in vivo studies, thatlog thresholds increase linearly with log electrode area, with a slopeof 0.7. However, as shown by FIG. 5 b, it is possible that a wider rangeof electrode sizes would make threshold differences as a function ofelectrode size more apparent. It is also possible, given the largeelectrode sizes used in this experiment that there was a “ringing” ofcurrent around electrode edges. Smaller electrodes would be expected tohave more even current distribution across the electrode surface.

Here we simply measured threshold: the current needed for stimulation tobe reliably detected. Useful prosthetic vision will, of course, requiresupra-threshold stimulation at higher current intensities that areneeded to elicit a threshold percept. Nonetheless, thresholds provide auseful indication of the lower limit beyond which it will be difficultto reduce electrode size. Our low threshold values suggest that evenwithout any reduction in threshold current amplitude with smallerelectrodes (as would be predicted from in vitro data, see above), it maystill be possible to use smaller electrodes than those used in thisstudy provided the array is close to the retinal surface. The resultsfrom S5 and S6 (where the surgeon was more experienced with tacking thearray to the retinal surface) both show thresholds consistently below100 μA (1 ms pulse) on a majority of the electrodes. Assuming platinumhas a conservative safe stimulation limit of 0.10 mC/cm², these dataimply that an electrode of just under 200 μm diameter would beacceptable. More advanced materials such as iridium oxide, with highersafe stimulation limits could safely permit an electrode of 65 μmdiameter. Reducing electrode size will permit more electrodes within thesame retinal area, translating into more pixels per degree of visualangle. Simulations of prosthetic vision suggest that more electrodes inthe central visual area of the retina may lead to a higher resolutionimage and better visual task performance.

Our data confirms in vitro retinal electrophysiology data suggestingthat the distance of electrode from the retina is a significant concern.We see a positive correlation between threshold current and electrodedistance from the retina (with a slope consistent with the hypothesisthat the electric field may diminish with the square of the distancefrom the electrode). This suggests that stimulus current requirementsare likely to increase significantly as the electrode lifts off theretina, resulting in large power consumption by the stimulator and aneed for significantly larger electrodes to safely supply current. Asecond concern is that the ability to produce small localized perceptsis also likely to be compromised by large separations between electrodesand the retinal surface.

We see a negative correlation between electrode distance and impedance,consistent with the notion that electrodes that are flush on the surfaceof the retina have higher impedances (due to the adjacent retinaltissue) than electrodes that have lifted from the retina (where salinesolution intervenes between the electrode and the retinal surface).

We believe that the distance of electrodes from the retinal surface issimilarly the common factor responsible for the negative correlationbetween threshold and impedance. Correlations between threshold andimpedance were significant in 5 out of the 6 individual subjects. Webelieve finding significant correlations within individual subjectsbetween threshold and impedance but not for OCT measurements likely tobe due to the fact that we had a much larger data set for impedance andthreshold values (OCT data were sparse due to collection difficulties).

The relationship between electrode distance from the retinal surface,impedance and threshold can been seen very clearly in S2, FIG. 6. Alifting of the array (observed using fundus imaging since OCT imagingwas not available at the time) led to an increase in thresholds and adecrease in impedances. After the array was reattached impedancesincreased and thresholds dropped. There was then a second graduallifting of the array from the retinal surface, which was againaccompanied by an increase in thresholds and a decrease in impedance.

We see an initial instability in impedance values shortly afterimplantation and stimulation that may be analogous to the rapid changesin impedance due to changes in the tissue surrounding the electrode andelectrochemical changes within the electrode that are found in cochlearimplants. However, because OCT measurements were only taken atrelatively infrequent intervals we cannot exclude the possibility thatthese changes in impedance were due to slight shifts in the position ofthe array as it ‘settled’ on the retina.

If long term stimulation led to retinal tissue damage or electrodecorrosion we might expect to see gradual increases in thresholds andchanges in impedance that were not associated with changes in theposition of the array. In subjects S4 and S6 OCT measurements were takenover an extended time period during which the array remained stable.During this time period changes in threshold and impedance values tendedto be relatively small (see FIG. 6). However it is nonetheless possiblethat that there may be subtle postoperative changes in either theelectrode surface or the retinal surface underlying the electrode thatwere not apparent in our data.

As better OCT imaging techniques become available it may be feasible, inthe next generation of retinal implants, to track short term changes inelectrode distance to the retina in the immediate post-operative period.Detailed information about the distance of the electrode from theretinal surface will allow a much finer characterization of therelationship between threshold, impedance and electrode position duringthe immediate post-implantation period.

Our data demonstrate that maintaining close proximity between theelectrode array and the retinal surface will be critical in developing asuccessful retinal implant. Thinner electrode structures may maintainmore stable proximity to the retina will become more tractable. With theuse of electrode arrays that are stable and flush on the retinalsurface, and more complex measures of perceptual performance than oursimple threshold measure, it is likely that other factors such aselectrode size, retinal deterioration and subject age may begin to playa more significant role.

Hence, the applicant has determined through experiment that, forelectrical stimulation of the retina, electrodes with high impedancerequire less current to create the perception of a pixel of light. Thisrelationship varies with electrode size. Impedance values may thereforeprovide a quick measure of the sensitivity of an electrode (i.e. theamount of current needed to elicit a percept on that electrode).

Impedance also varies with the height of the electrode array from theretinal surface. This means that impedance measurements can be used toestimate whether the array has shifted on the retina, and to estimatethe distance of various parts of the array from the retinal surface in aless time-consuming way that direct measurements of retinal position(such as OCT).

Threshold varies with the height of the array from the retinal surface.Therefore, if measuring the height of each electrode from the retinalsurface is possible, it is possible to estimate electrode sensitivitiesbased on their height from the retinal surface.

Impedance can also vary across the retinal surface due to disease andphysical irregularities. It is advantageous to provide a surgeon withreal time impedance information during surgery to aid the surgeon inplacing the stimulating electrode array.

It should also be noted that it is not always necessary to test everyelectrode. As array resolution becomes greater, it will becomeincreasingly difficult to test every electrode. Geographically relatedelectrodes tend to have similar impedance, electrode-retinal height, andthreshold of perception. Hence, impedance, electrode-retinal height, andthreshold of perception can be extrapolated from testing sampleelectrodes.

FIG. 8, depicts a computer screen optimized for providing impedanceinformation in a clear and simple manner. The screen provides a grid ofdots 81, one dot corresponding to each electrode. The dots on thecomputer screen are in the physical layout as the electrode array. Aseries of colors ranging through the color spectrum are assigned toimpedance ranges and show in a key 82 to the left of the dots 81. Eachtime an impedance measurement is taken, the dot corresponding to themeasured electrode is colored according to the measured impedance. Afterthe entire array of electrodes have been measured, the physician canquickly scan the hue of the screen to assess the placement of theelectrodes or any areas that have higher impedance than others. Thisallows the surgeon to quickly asses multiple locations while implantingan electrode array. Alternatively, an audible signal where pitch isproportional to mean frequency of the electrodes may allow a surgeon tolook at the array placement while receiving impedance feedback.

It is also advantageous to further emphasize electrodes out ofacceptable range by placing an X 85 across the corresponding dot. Themeasurement may be continuous or activated manually by a measureimpedance button 83 on the screen. An all waveforms button 84, displaysthe complete stimulation wave form for analysis as described withrespect to FIG. 11 below. The information screen also includesinformation 86 on the experimenter, subject, proper communications, andif the implant is currently stimulating.

The implanted neural stimulator provides bidirectional data through anRF link. Stimulation information is provided to the implanted device andtelemetry information including voltage drops, from which impedance iscalculated, is sent back. Impedance measurement is generally conductedsub-threshold. Although stimulation may be supra-threshold, it should below enough to not disturb the subject. A stimulation current too smallto create a percept, will still return a voltage drop measurement thatcan be used to calculate impedance using Ohms law.

FIG. 9 describes the testing procedure. As stated above, the testing canbe automatically repeated or activated by the press of a button. Hencethe testing software first determines the mode 90. In continuous modethe software continuously test a timer 92 for the next testing event. Inmanual mode, the software test for the press of the test button 94.Either will start the test cycle. First, the electrode counter E is setto 0 96, and incremented 98. Electrode E is stimulated 100 with asub-threshold stimulation pulse. The voltage drop is measured 102 andreturned to the external system 104. If E is not equal to the totalnumber of electrodes 106, the process is repeated until it is. Uponmeasuring all electrodes the software returns to check the mode again90.

FIG. 10 shows a method of identifying defective electrodes by impedanceand deactivating those defective electrodes. The process begins byselecting the first electrode 110. The selected electrode is stimulatedat a predetermined current and pulse width after the best gain settinghas been identified for that electrode 112. The system then performs thefollowing calculations 114:R _(S1) =v2−v ₁ /I;C _(S)=(I*pulse width)/v ₅ −v ₂;Z=(V ₅ −V ₁)/I;R _(S2) =V ₅ −V ₆ /I.f(S₁, S₂, S₃) which can be one of a number of functions includeincluding linearity, monotonicity, or similar function. V₁₋₆ are voltagedrops taken at various points in the stimulation waveform (see FIG. 11).S1, S2, S3 are the incremental slopes of the capacitive charging portionof the voltage measurement. If R_(S1) is less that 1.5 KΩ 116, thesystem calculates R_(S2) 118. If R_(S2) is less than 1.5 KΩ 120, currentis doubled 122 and the best gain setting is found 124 and the electrodeis stimulated again. This doubling of the measurement current iscontinued till it reaches the maximum charge density safety limit. Whenthe current reaches the safety limit without a good measurement beingobtained, the electrode is marked as compromised. If R_(S2) is greateror equal to 1.5 KΩ, 120, R_(S1) is set to R_(S2) 126. If Z is greaterthan 45 KΩ and R_(S1) is less than 1.5 KΩ 128 then the electrode ismarked as compromised 130. If not all electrodes have been tested 132then the next electrode is selected 134. If all electrodes have beentested 132, the process returns to the first electrode 136. If Z is lessthan 10 KΩ, 138, the electrode is marked as in the low impedance group140. Otherwise it is marked as in the high impedance group 142. Thesystem computes the median Z and standard deviation for the lowimpedance group 144 and the median Z and standard deviation for the highimpedance group 146. If Z for an electrode minus the median Z is greaterthan or equal to four times the standard deviation 148, then calculateC_(S) (or alternatively calculate the function of S described above andmark the electrode broken if the function pass criteria is violated)150. If C_(S) is greater than 250 nF 152, the electrode is marked broken154. Alternatively, if an electrode is the high impedance group and Zfor the electrode minus the median Z is greater than or equal to fourtimes the standard deviation 156, then C_(S) is calculated (oralternatively calculate the function of S described above and mark theelectrode broken if the function pass criteria is violated) 150 and ifC_(S) is greater than 250 nF 152, the electrode is marked broken 154.Otherwise, the electrode is marked good 168.

If an electrode is in the low impedance group and its Z minus the medianZ is less than the negative of four times the standard deviation 158,then calculate C_(S) (or alternatively calculate the function of Sdescribed above and mark the electrode shorted and if the function passcriteria is violated) 160. If CS is greater than 250 nF 162, theelectrode is marked shorted 164. Alternatively, if an electrode is thehigh impedance group and Z for the electrode minus the median Z is lessthan the negative of four standard deviations 166, then C_(S) iscalculated (or alternatively calculate the function of S described aboveand mark the electrode shorted and if the function pass criteria isviolated) 160 and if C_(S) is greater than 250 nF 162, the electrode ismarked shorted 164. Otherwise, the electrode is marked good 168. Hence,a fully automated system can measure impedance, predict a fitting curveand identify defective electrodes without clinician intervention.

FIG. 11 depicts a stimulation pulse further illustrating themeasurements described in FIG. 10. Points labeled one through 7 arevoltage measurement points. Hence V₁ is the voltage drop measured atpoint 1. S₁ is the slope of the curve between V₂ and V₃, S₂ is the slopeof the curve between V₃ and V₄ and S₃ is the slope of the curve betweenV₄ and V₅

Accordingly, what has been shown is an improved method of making aneural prosthesis and improved method of stimulating neural tissue.While the invention has been described by means of specific embodimentsand applications thereof, it is understood that numerous modificationsand variations could be made thereto by those skilled in the art withoutdeparting from the spirit and scope of the invention. In particular, thepreferred embodiment describes a retinal prosthesis for artificialvision. It should be obvious to one skilled in the art that theinvention has broad applicability to other types of neural stimulation.It is therefore to be understood that within the scope of the claims,the invention may be practiced otherwise than as specifically describedherein.

1. A neural stimulation system comprising: a plurality of electrodessuitable to stimulate neural tissue; means form measuring impedance ofat least one of said plurality of electrodes; and means for estimating athreshold of perception based on said impedance.
 2. The neuralstimulation system according to claim 1, further comprising means forcommunicating said impedance to a clinician.
 3. The neural stimulationsystem according to claim 1, further comprising means for measuringelectrode height; and means for estimating a threshold of perceptionbased on said impedance and said electrode height.
 4. The neuralstimulation system according to claim 3, further comprising means formeasuring retinal thickness; and means for estimating a threshold ofperception based on said impedance, said electrode height and saidretinal thickness.
 5. The neural stimulation system according to claim4, further comprising means for estimating a brightness response curvebased on said impedance, said electrode height and said retinalthickness.
 6. A neural stimulation system comprising: a plurality ofelectrodes suitable to stimulate neural tissue; means form measuringelectrode height of at least one of said plurality of electrodes; andmeans for estimating a threshold of perception based on said electrodeheight.
 7. The neural stimulation system according to claim 6, furthercomprising means for communicating said electrode height to a clinician.8. The neural stimulation system according to claim 6, furthercomprising means for measuring impedance between at least one electrode;and means for estimating a threshold of perception based on saidimpedance and said electrode height.
 9. The neural stimulation systemaccording to claim 8, further comprising means for measuring retinalthickness; and means for estimating a threshold of perception based onsaid impedance, said electrode height and said retinal thickness. 10.The neural stimulation system according to claim 9, further comprisingmeans for estimating a brightness response curve based on saidimpedance, said electrode height and said retinal thickness.
 11. Theneural stimulation system according to claim 6, wherein said means formeasuring electrode height is OCT.
 12. The neural stimulation systemaccording to claim 6, wherein said means for measuring electrode heightis ultrasound.
 13. A neural stimulation system comprising: a pluralityof electrodes suitable to stimulate neural tissue; means form measuringimpedance of at least one of said plurality of electrodes; means forcommunicating said impedance to an external device; and means in saidexternal device for displaying said impedance to a user.
 14. The neuralstimulation system according to claim 13, wherein said means in saidexternal device for displaying said impedance to a user is a graphicalrepresentation of said plurality of electrodes.
 15. The neuralstimulation system according to claim 13, wherein said means in saidexternal device for displaying said impedance to a user displaysimpedance by sound.
 16. The neural stimulation system according to claim13, wherein said means in said external device for displaying saidimpedance to a user displays impedance by color.
 17. The neuralstimulation system according to claim 13, wherein said means in saidexternal device for displaying said impedance to a user displaysimpedance by graphical symbol.
 18. A method of determining properplacement of a neural stimulation electrode array comprising: placing anelectrode array in proximity of neural tissue; measuring impedanceacross the electrode array; and determining, by the impedance, theproper placement of the electrode array.
 19. The method according toclaim 18, further comprising: placing said electrode array in aplurality of locations; measuring impedance across the electrode arrayin each location; and determining, by the impedances, the best placementof the electrode array.
 20. A method of fitting a neural stimulationdevice comprising: providing a plurality of electrodes suitable tostimulate neural tissue; measuring impedance of at least one of saidplurality of electrodes; and estimating a threshold of perception basedon said impedance.
 21. The method according to claim 20, furthercomprising communicating said impedance to a clinician.
 22. The methodaccording to claim 20, further comprising: measuring electrode height;and estimating a threshold of perception based on said impedance andsaid electrode height.
 23. The method according to claim 22, furthercomprising measuring retinal thickness; and estimating a threshold ofperception based on said impedance, said electrode height and saidretinal thickness.
 24. The method according to claim 23, furthercomprising estimating a brightness response curve based on saidimpedance, said electrode height and said retinal thickness.
 25. Themethod according to claim 20, further comprising estimating threshold ofperception, based on said impedance for other geographically relatedelectrodes.
 26. A method of fitting a neural stimulation systemcomprising: proving a plurality of electrodes suitable to stimulateneural tissue; measuring electrode height of at least one of saidplurality of electrodes; and estimating a threshold of perception basedon said electrode height.
 27. The method according to claim 26, furthercomprising communicating said electrode height to a clinician.
 28. Themethod according to claim 27, further comprising: measuring impedancebetween at least one electrode; and estimating a threshold of perceptionbased on said impedance and said electrode height.
 29. The methodaccording to claim 28, further comprising: measuring retinal thickness;and estimating a threshold of perception based on said impedance, saidelectrode height and said retinal thickness.
 30. The method according toclaim 29, further comprising estimating a brightness response curvebased on said impedance, said electrode height and said retinalthickness.
 31. The method according to claim 26, wherein measuringelectrode height is by OCT.
 32. The method according to claim 26,wherein said measuring electrode height is by ultrasound.
 33. A methodof fitting and adjusting a neural stimulation device comprising:providing a plurality of electrodes suitable to stimulate neural tissue;measuring impedance of at least one of said plurality of electrodes;communicating said impedance to an external device; and displaying saidimpedance to a user.
 34. The method according to claim 33, whereindisplaying said impedance to a user is by graphical representation ofsaid plurality of electrodes.
 35. The method according to claim 33,wherein displaying said impedance to a user is a graphicalrepresentation of said plurality of electrodes.
 36. The method accordingto claim 33, wherein displaying said impedance to a user is by color.37. The method according to claim 33, wherein displaying said impedanceto a user is by graphical symbol.
 38. A method of determining adefective electrode in a neural stimulation device comprising: providinga plurality of electrodes in proximity to neural tissue; stimulatingneural tissue with a biphasic pulse on said plurality of electrodes;measuring voltage drops at a plurality of point during said biphasicpulse stimulation; calculating a function of said voltage drops for saidplurality of electrode; comparing calculated results for said pluralityof electrodes; and determining that electrodes defective if itscalculated results deviates significantly from the mean/median of allcalculated results.
 39. The method according to claim 38, where saidfunction is the voltage change between said points divided by current.39. The method according to claim 38, wherein said function is alinearity function of the slope of said voltage drop measurements. 40.The method according to claim 38, wherein said function is amonotonicity function of the slope of said voltage drop measurements.41. The method according to claim 38, wherein varies is varies by morethan four standard deviations.
 42. The method according to claim 38,wherein said function is a function of voltage drop and capacitance. 43.The method according to claim 38, further comprising determining that anelectrode is defective if its calculated results exceeds fixed upperand/or lower limits.